The marker, monocyte chemoattractant protein 1 (MCP-1), and its mRNA were elevated in urine samples of both mice and humans with acute kidney injury in a study led by Richard A. Zager, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues.

The biomarker appeared to be more specific for acute kidney injury than the gold-standard urinary marker neutrophil gelatinase-associated lipocalin (NGAL), they reported online in the Journal of the American Society of Nephrology.

The hope is that early detection can lead to early therapy and prevent acute renal failure, but larger prospective studies are needed to determine clinical utility, the researchers noted.

They first studied mice injected with the nephrotoxic agent maleate to simulate acute kidney injury.

Within four hours, the mice showed an approximately 15-fold increase in plasma MCP-1 concentrations compared with a twofold increase in plasma NGAL, pointing to "MCP-1's high sensitivity as an acute kidney injury biomarker," according to the researchers.

To show potential for use as a urinary marker, the researchers measured mRNAs of both markers in urine at four hours after maleate injection. MCP-1 mRNA was elevated nine-fold compared with baseline, while NGAL mRNA had risen threefold.

These urinary changes roughly paralleled those in renal cortical mRNA and their plasma protein levels.

"This suggests that urinary mRNA levels could conceivably serve as a semiquantitative surrogate marker of intrarenal gene transcription," Zager's group noted in the paper, although cautioning that "at least some of these ... mRNA increases likely reflected nonspecific tubular cell sloughing."

Together these findings suggested that both biomarkers were relatively nonspecific for structural proximal tubular injury, though MCP-1 had some advantage in this regard, the researchers suggested.

MCP-1 also showed at least comparable clinical utility compared with NGAL as an acute kidney injury marker when examined in urine samples from 10 intensive care unit patients with progressive azotemia due to kidney injury who ultimately required hemodialysis.

Their urinary MCP-1 concentrations did not overlap with those of 10 ICU patients with comparable critical illness severity scores but no azotemia, nor those of 10 healthy volunteers (P<0.01 between ICU groups and non-AKI critically ill patients versus controls).

By contrast, NGAL levels did overlap substantially for the acute kidney injury patients and controls, although they were still significantly different between groups (P<0.03 and P<0.05, respectively).

MCP-1 mRNA in the acute kidney injury patients were elevated nine-fold compared with the ICU controls (P<0.02) whereas NGAL mRNA levels were no different between the two groups.

Notably, total urine protein concentrations -- a standard biomarker of glomerulopathy -- rivaled either of the other specific urinary protein markers in pointing to acute kidney injury, and urinary albumin concentrations also significantly differentiated the critically ill populations with and without acute kidney injury.

"Indeed, we suggest that, given their widespread availability, urine total protein and/or albumin levels can serve as important reference tests when interpreting urinary levels of more specific acute kidney injury protein biomarkers," Zager's group wrote in the paper.

The researchers cautioned that they made no attempts to prevent degradation of urinary mRNA other than simply freezing the samples, so using mRNA preservation techniques could increase the utility of the test.

Also, biomarker data interpretation may have been confounded by the apparent spectrum of renal damage in critically ill patients, since those without acute kidney injury still had higher MCP-1, NGAL, and mRNA values than the healthy controls, they noted.

The group found that factoring in urine creatinine didn't boost the utility of urinary NGAL or MCP-1, which may have simply reflected that the urine creatinine concentrations were essentially identical in the two critically ill populations, they added.

The investigators also provided the first "proof-of-concept" evidence that assessment of urinary histones that activate the gene that produces MCP-1 could be detected in human urine samples.

Urinary mRNA of the histone-modifying enzyme BRG-1 were elevated in the critically ill patients with acute kidney injury compared with those without acute kidney injury. Also, the gene-activating histone change known as H3K4 trimethylation could be detected in urinary MCP-1 gene fragments in urine with chromatin immunoprecipitation assay, with significant differences between the two critically ill groups (P<0.035).

With further confirmation, urinary histone assessment could be "a highly useful, and novel tool for studying pathogenetic mechanisms in patients with kidney disease," Zager and colleagues concluded.

The study was supported by grants from the National Institutes of Health and from nonrestricted research funds from the Kidney Research Institute.

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